Behavior is shaped by interactions among a large number of genes. To understand the genetic underpinnings of variation in behavior, its underlying genetic architecture must be dissected and the specific genetic polymorphisms that cause functional differences in behavior must be identified. Chemosensory behavior is an excellent system for addressing these goals because of recent advances uncovering both the genetic factors and neural coding involved. Chemosensory perception is an important human health issue. Loss of olfactory acuity in the elderly can compromise nutrition and quality of life and olfactory deficits are diagnostic of several neurological disorders, such as Alzheimer's. Human chemosensory perception is variable, with some specific anosmias genetically determined. Yet despite advances in our understanding of odor coding, the molecular basis of variation in olfactory perception at the level of the primary odorant receptors remains poorly understood. The similarity of odor coding in both vertebrates and insects suggests analogous principles underlie the organization of their olfactory systems. In both systems, families of odorant receptors are used to discriminate among a vast repertoire of odorants. The Drosophila olfactory system, however, is quantitatively less complex and the use of Drosophila readily allows for the control of genetic background and environment. This system provides us with an excellent opportunity for elucidating how molecular polymorphisms in odorant receptors contribute to variation in olfactory behavior. This application proposes three specific aims: (1) to measure natural variation in olfactory behavior in a population of wild-derived inbred lines of Drosophila melanogaster;(2) to quantify the contribution of molecular variation in odorant receptors to natural variation in behavior, and (3) to test the functional effects of allelic variation in odorant receptors. Behavioral variation to an array of odorants will be assessed and single nucleotide polymorphisms will be identified by sequencing the odorant receptor gene family. Polymorphisms contributing to natural variation in olfactory behavior will then be identified and further validated using crosses among wild-derived lines. In addition, functional studies of the underlying mechanisms that contribute to variation in olfactory behavior will be conducted. These experiments will provide new insights into how ensembles of receptors that recognize defined odorants contribute to natural variation in behavior at the level of single nucleotide polymorphisms. More broadly, the results will provide a model for understanding how genetic variation in candidate loci results in functional differences in behavior and the mechanisms underlying the origin and maintenance of variation in complex traits in nature. PUBLIC HEALTH RELEVANCE: Chemosensory perception is an important human health issue as loss of olfactory acuity in the elderly can compromise nutrition and quality of life and olfactory deficits are diagnostic of several neurological disorders. Yet despite advances in our understanding of odor coding, the molecular basis of variation in olfactory perception at the level of the primary odorant receptors remains poorly understood. The proposed research addresses this question by dissecting the underlying genetic architecture of olfactory behavior and examining the mechanism(s) by which variation in candidate behavioral loci shape behavioral variation.